Implantable polymeric device for sustained release of buprenorphine

ABSTRACT

The present invention provides compositions, methods, and kits for treatment of opiate addiction and pain. The invention provides a biocompatible nonerodible polymeric device which releases buprenorphine continuously with generally linear release kinetics for extended periods of time. Buprenorphine is released through pores that open to the surface of the polymeric matrix in which it is encapsulated. The device may be administered subcutaneously to an individual in need of continuous treatment with buprenorphine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/222,842, filed Dec. 17, 2018, which is a continuation of 15/667,770,filed Aug. 3, 2017, now abandoned, which is a continuation of U.S.patent application Ser. No. 15/165,641, filed May 26, 2016, nowabandoned, which is a continuation of U.S. patent application Ser. No.14/091,296, filed Nov. 26, 2013, now abandoned, which is a continuationof U.S. patent application Ser. No. 13/691,379, filed Nov. 30, 2012, nowabandoned, which is a continuation of U.S. patent application Ser. No.11/801,302, filed May 8, 2007, now abandoned, which is a continuation ofU.S. patent application Ser. No. 10/453,377, filed Jun. 2, 2003, nowU.S. Pat. No. 7,736,665 issued on Jun. 15, 2010, which claims thebenefit of U.S. Provisional Patent Application Ser. No. 60/384,733,filed May 31, 2002, the disclosures of which are incorporated herein byreference in their entirety.

p STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant NumberMH060037 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

TECHNICAL FIELD

The invention provides a nonbioerodible, polymeric device forsubcutaneous implantation and sustained release of buprenorphine fortreatment of opiate addiction or pain.

BACKGROUND OF THE INVENTION

Buprenorphine, a semi-synthetic opiate classified as a “partial agonist”behaves very much like classical mu agonists such as morphine, exertingan analgesic effect through high affinity binding to mu subclass opiatereceptors in the central nervous system.

Buprenorphine has been used as an analgesic for treatment of moderate tosevere pain in postoperative cancer patients. Therapeutic dosesadministered by intravenous and intramuscular routes range from 0.3 to0.6 mg. Buprenorphine produces effects similar to morphine but is 25-40times more potent and has a large therapeutic index. Buprenorphinestimulates the mu opiate receptors in the brain and produces effectsassociated with other mu agonists such as morphine. Such effects includeanalgesia, euphoria, sedation, and respiratory depression. For thisreason, oral buprenorphine formulations have the potential for misuse(i.e., diversion for recreational, rather than therapeutic, purposes),making them unsuitable for use as a take-home medication.

Many patients with chronic pain require long-term continuous dosing withopiate analgesics. Effective treatment often necessitates the ingestionof multiple tablets per day. Compliance with this dosing scheme is oftenpoor. Further, enteral drug delivery is poorly tolerated or prohibitedin patients with particular indications, such as some patients withcancer-related pain in whom continuous drug delivery is a necessity.However, continuous parenteral delivery of opiate analgesics isexpensive, cumbersome, and dependent upon the availability ofrefrigeration, catheters, pumps, and trained personnel. Further,concerns over drug diversion for illicit use often limits availabilityof opiate analgesics. An oral tablet containing a combination ofbuprenorphine and naloxone, an opiate receptor antagonist, has beendeveloped to address this issue (see, e.g., U.S. Pat. No. 4,935,428). Ifan opiate addict attempts to abuse the combination tablet by dissolvingit and injecting it intravenously, unpleasant withdrawal symptomsbrought on by the naloxone component will result. However, opiateantagonists such as naloxone may reduce the analgesic effectiveness ofbuprenorphine to those who are using it therapeutically for pain reliefand such antagonists may cause undesirable side effects. Thus, there isa need for an improved buprenorphine formulation which is administrableto those in need of analgesia but which provides a lower potential forabuse.

Buprenorphine has also been studied as a treatment for addiction toheroin and other opiates. Opiate addiction is a major societal problemthroughout the world. The general treatment program for such addictionincludes incorporation of a drug substitute, e.g., methadone, into anoral formulation for administration to the drug addict. Typically, suchdrug substitutes function by binding to receptors specific for the drugof abuse. The effectiveness of such treatment depends largely uponadherence to an established treatment schedule. Often, poor compliancewith dosing regimens complicates treatment. Further, the cost of suchtherapy is significant, a large portion of the cost relating to frequentclinic visits and the monitoring of urine tests to assure compliancewith drug dosing, as well as pharmacy charges relating to dispensing ofmethadone. Another problem with oral dosage forms such as powders ortablets is that they can be dissolved in water and concentrated toprovide a solution which may be injected by the addict in lieu of thedrug of abuse. A means for long-term continuous administration of a drugsuitable for treatment of opiate dependency in a form that is notsubject to potential abuse, would significantly reduce the complianceproblems encountered in drug addiction treatment programs.

Buprenorphine's unique effects and pharmacology make it a clinicallyattractive treatment option for opiate dependency. For example,buprenorphine produces less euphoria than morphine and heroin. Whencompared with other opiates, it also causes a significantly lower degreeof sedation. Further, direct dependence studies have shown littlephysical dependence upon withdrawal of the drug.

There is a need for a buprenorphine formulation, suitable for long-term,continuous administration, that will improve compliance for both painrelief and drug dependency treatment regimens. There is also a need fora buprenorphine formulation that will reduce abuse potential, and inwhich the addition of an antagonist such as naloxone will not benecessary.

BRIEF SUMMARY OF THE INVENTION

The invention provides compositions (i.e., implantable polymericdevices), methods, and kits for treatment of opiate addiction and pain.

In one aspect the invention provides an implantable device for treatingopiate addiction, comprising buprenorphine and a biocompatible,nonerodible polymeric matrix, wherein said buprenorphine is encapsulatedwithin said matrix, and wherein when said implantable device isimplanted subcutaneously in a mammal, said buprenorphine is continuouslyreleased in vivo over a sustained period of time through pores that opento the surface of said matrix at a rate that results in a steady stateplasma buprenorphine level of at least about 0.1 ng/ml, typically in therange of about 0.1 to about 70 ng/ml. In some embodiments, the steadystate plasma buprenorphine level is about 1 to about 10 ng/ml. In otherembodiments, the steady state plasma buprenorphine level is about 1 toabout 6 ng/ml. In some embodiments, the polymeric matrix comprisesethylene vinyl acetate copolymer (EVA). In some embodiments wherein theimplantable device comprises EVA, the vinyl acetate content is about 33%by weight. The implantable devices generally comprise about 10% to about85%, often about 50% to about 75% buprenorphine. In one embodiment, theimplantable device comprises about 50% buprenorphine. In anotherembodiment, the implantable device comprises about 75% buprenorphine. Invarious embodiments, the sustained period of time for buprenorphinerelease is from about 3 months to about 1 year, or longer, e.g., atleast about 3, 6, 9, or 12 months. In some embodiments, the implantabledevice for treatment of opiate addiction is produced by an extrusionprocess. In one embodiment, extruded devices comprise dimensions ofabout 2.4 mm in diameter and about 2.6 cm in length. In otherembodiments, extruded devices comprise dimensions of about 2 to about 3mm in diameter and about 2 to about 3 cm in length. In furtherembodiments, extruded devices comprises dimensions of about 0.5 to about7 mm in diameter and about 0.5 to about 10 cm in length. In someembodiments in which extruded devices comprise dimensions of about 2.4mm in diameter and about 2.6 cm in length, the devices each releaseabout 1 mg buprenorphine per day in vitro.

In another aspect, the invention provides an implantable device fortreating pain, comprising buprenorphine and a biocompatible, nonerodiblepolymeric matrix, wherein said buprenorphine is encapsulated within saidmatrix, and wherein when said implantable device is subcutaneouslyimplanted in a mammal, said buprenorphine is continuously released invivo over a sustained period of time through pores that open to thesurface of said matrix at a steady state rate of at least about 0.1 mgper day, generally in the range of about 0.1 to about 5 mg per day. Insome embodiments, the steady state rate of buprenorphine release isabout 0.3 mg per day. In some embodiments, the polymeric matrixcomprises EVA. In some embodiments wherein the implantable devicecomprises EVA, the vinyl acetate content is about 33% by weight. Theimplantable devices generally comprise about 10% to about 85%, oftenabout 50% to about 75% buprenorphine. In one embodiment, the implantabledevice comprises about 50% buprenorphine. In another embodiment, theimplantable device comprises about 75% buprenorphine and about 25% EVA.In various embodiments, the sustained period of time for buprenorphinerelease is from about 3 months to about 1 year, or longer, e.g., atleast about 3, 6, 9, or 12 months. In some embodiments, the implantabledevice for treatment of pain is produced by an extrusion process. In oneembodiment, extruded devices comprise dimensions of about 2.4 mm indiameter and about 2.6 cm in length. In other embodiments, extrudeddevices comprise dimensions of about 2 to about 3 mm in diameter andabout 2 to about 3 cm in length. In further embodiments, extrudeddevices comprises dimensions of about 0.5 to about 7 mm in diameter andabout 0.5 to about 10 cm in length. In some embodiments in whichextruded devices comprise dimensions of about 2.4 mm in diameter andabout 2.6 cm in length, the devices each release about 1 mgbuprenorphine per day in vitro.

In one aspect, the invention provides a method for treatment of opiateaddiction, comprising administering at least one implantable device fortreatment of opiate addiction, as described above, subcutaneously,wherein each of said at least one implantable devices comprisesbuprenorphine encapsulated within a biocompatible, nonerodible polymericmatrix, wherein said buprenorphine is continuously released in vivo overa sustained period of time through pores that open to the surface ofsaid matrix at a rate that results in a steady state plasmabuprenorphine level of at least about 0.1 ng/ml, generally about 0.1 toabout 70 ng/ml. In some embodiments, the steady state plasma level ofbuprenorphine is about 1 to about 10 ng/ml. In other embodiments, thesteady state plasma level of buprenorphine is about 1 to about 6 ng/ml.In one embodiment, the method includes a multiplicity of individualimplantable devices, wherein the combination of the implantable devicescontinuously releases buprenorphine in vivo over a sustained period oftime at a steady state rate that results in a plasma buprenorphine levelof about 0.1 to about 70, about 1 to about 10, or about 1 to about 6ng/ml. In some embodiments, the polymeric matrix comprises EVA. In oneembodiment, implantable devices comprise about 75% buprenorphine andabout 25% EVA. In another embodiment, implantable devices comprise about50% buprenorphine. In some embodiments wherein implantable devicescomprise EVA, the vinyl acetate content is about 33% by weight. Invarious embodiments, the sustained period of time for buprenorphinerelease is from about 3 months to about 1 year, or longer, e.g., atleast about 3, 6, 9, or 12 months. In some embodiments, implantabledevices for treatment of opiate addiction are produced by an extrusionprocess. In one embodiment, extruded devices comprise dimensions ofabout 2.4 mm in diameter and about 2.6 cm in length. In otherembodiments, extruded devices comprises dimensions of about 2 to about 3mm in diameter and about 2 to about 3 cm in length. In furtherembodiments, extruded devices comprise dimensions of about 0.5 to about7 mm in diameter and about 0.5 to about 10 cm in length. In someembodiments in which extruded devices comprises dimensions of about 2.4mm in diameter and about 2.6 cm in length, the devices each releaseabout 1 mg buprenorphine per day in vitro. In methods of the invention,the implantable devices are administered by subcutaneous implantation.In various embodiments, the devices are subcutaneously implanted at asite selected from the group consisting of the upper arm, the back, andthe abdomen.

In another aspect, the invention provides a method for treatment ofpain, comprising administering at least one implantable device fortreatment of pain, as described above, subcutaneously, wherein each ofsaid at least one implantable devices comprises buprenorphineencapsulated within a biocompatible, nonerodible polymeric matrix,wherein said buprenorphine is continuously released in vivo over asustained period of time through pores that open to the surface of saidmatrix at a steady state rate of at least about 0.1 mg per day, often inthe range of about 0.1 to about 5 or about 0.2 to about 1 mg per day. Insome embodiments, the steady state rate of buprenorphine release isabout 0.3 mg per day. In one embodiment, the method includes amultiplicity of individual implantable devices, wherein the combinationof the implantable devices continuously releases buprenorphine in vivoover a sustained period of time at a steady state rate of about 0.1 toabout 5, about 0.2 to about 1, or about 0.3 mg per day. In someembodiments, the polymeric matrix comprises EVA. In one embodiment,implantable devices comprise about 75% buprenorphine and about 25% EVA.In another embodiment, implantable devices comprise about 50%buprenorphine. In some embodiments wherein implantable devices compriseEVA, the vinyl acetate content is about 33% by weight. In variousembodiments, the sustained period of time for buprenorphine release isfrom about 3 months to about 1 year, or longer, e.g., at least about 3,6, 9, or 12 months. In some embodiments, implantable devices fortreatment of pain are produced by an extrusion process. In methods ofthe invention, the implantable devices are administered by subcutaneousimplantation. In various embodiments, the devices are subcutaneouslyimplanted at a site selected from the group consisting of the upper arm,the back, and the abdomen.

In one aspect, the invention provides a kit for use in treatment ofopiate addiction, comprising at least one implantable device fortreatment of opiate addiction, as described above, comprisingbuprenorphine encapsulated within a biocompatible, nonerodible polymericmatrix, wherein when said at least one implantable device is implantedsubcutaneously in a mammal, said buprenorphine is continuously releasedin vivo over a sustained period of time through pores that open to thesurface of said matrix at a rate that results in a steady state plasmalevel of about 0.1 to about 70 ng/ml, and instructions for use. In someembodiments, the steady state plasma level is about 1 to about 10 ng/ml.In other embodiments, the steady state plasma level is about 1 to about6 ng/ml. In some embodiments, kits include a multiplicity of individualimplantable devices, wherein when said multiplicity of devices isimplanted subcutaneously in a mammal, the combination of the implantabledevices continuously releases buprenorphine in vivo over a sustainedperiod of time at a rate that results in a steady state plasma level ofabout 0.1 to about 70, often about 1 to about 10, more often about 1 toabout 6 ng/ml. In one embodiment, each of the individual implantabledevices releases buprenorphine at a rate of about 1 mg per day in vitro.In some embodiments, the polymeric matrix comprises EVA. In variousembodiments, implantable devices comprise about 10 to about 85%buprenorphine. In some embodiments wherein implantable devices compriseEVA, the vinyl acetate content is about 33% by weight.

In another aspect, the invention provides a kit for use in treatment ofpain, comprising at least one implantable device for treatment of pain,as described above, comprising buprenorphine encapsulated within abiocompatible, nonerodible polymeric matrix, wherein when said at leastone implantable device is implanted subcutaneously in a mammal, saidbuprenorphine is continuously released in vivo over a sustained periodof time through pores that open to the surface at a steady state rate ofat least about 0.1 mg per day, generally in the range of about 0.1 toabout 5 or about 0.2 to about 1 mg per day, and instructions for use. Inone embodiment, the steady state rate of buprenorphine release is about0.3 mg per day. In some embodiments, kits include a multiplicity ofindividual implantable devices, wherein when said multiplicity ofdevices is implanted subcutaneously in a mammal, the combination of theimplantable devices continuously releases buprenorphine in vivo over asustained period of time at a rate of about 0.1 to about 5, 0.2 to about1, or about 0.3 mg per day. In some embodiments, the polymeric matrixcomprises EVA. In various embodiments, implantable devices compriseabout 10 to about 85% buprenorphine. In some embodiments whereinimplantable devices comprise EVA, the vinyl acetate content is about 33%by weight.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B depict in vitro release of buprenorphine over timefrom a single irradiated extruded rod containing 75% buprenorphine HCland 25% EVA (33% vinyl acetate). FIG. 1A shows the average cumulativerelease of buprenorphine HCl in 0.5% SDS at 37° C. FIG. 1B shows theaverage daily release of buprenorphine HCl in 0.5% SDS at 37° C.

FIG. 2 depicts in vivo release of buprenorphine from devices of theinvention implanted subcutaneously in dogs for 84 days. Two devices,each with dimensions of about 2.6 cm in length and about 2 mm indiameter, and containing 75% buprenorphine HCl and 25% EVA (33% vinylacetate), were implanted in each dog.

FIG. 3 depicts in vivo release of buprenorphine when 8, 16, or 24implantable devices were implanted subcutaneously in dogs for 8 months.

FIG. 4 depicts the steady state plasma concentration of buprenorphineachieved when 2, 8, 16, or 24 implantable devices were implantedsubcutaneously in dogs.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a biocompatible, nonerodible polymeric device,which permits controlled, sustained release of buprenorphine overextended periods of time when implanted subcutaneously in an individualin need of treatment.

Continuous release of a compound in vivo over an extended duration maybe achieved via implantation of a device containing the compoundencapsulated in a nonerodible polymeric matrix. Examples of implantable,nonerodible polymeric devices for continuous drug release are describedin, e.g., U.S. Pat. Nos. 4,883,666, 5,114,719, and 5,601,835.Implantable devices improve compliance with drug dosing regimens, due tocontinuous release of the drug from the polymeric matrix, and reduceabuse potential since such devices are not as subject to diversion asother formulations, such as, for example, oral dosage forms.

Implantation of the device and extended release of buprenorphine limitsor prevents diversion of the drug to nonintended users and improvescompliance with dosing regimens, eliminating the need for repeatedinjections or ingestion of pills or tablets. An implantable,sustained-release device according to the present invention also permitsachievement of more constant blood levels of buprenorphine thaninjectable or oral dosage forms, thereby minimizing side effects.

Previous vehicles for long term delivery of buprenorphine have includedbiodegradable polymers (U.S. Pat. No. 5,486,362). However, in contrastto the present invention, such polymers do not release compounds atlinear rates for extended time periods of several months or longer,because channels form in the matrix as it erodes, resulting in increasedrelease rates over time. The present invention includes a biocompatible,nonerodible polymer that exhibits generally linear release kinetics forbuprenorphine in vivo, after an initial burst.

Implantable Polymeric Devices for Treatment of Opiate Addiction or Pain

The invention includes implantable devices for treatment of opiateaddiction or pain, including buprenorphine encapsulated in a polymeric,nonerodible matrix. As used herein, “buprenorphine” refers tobuprenorphine free base and pharmaceutically acceptable salts thereof,such as buprenorphine HCl, and norbuprenorphine. Incorporation ofbuprenorphine into the polymeric matrix causes the formation of a seriesof interconnecting channels and pores that are accessible to the surfacefor release of the drug. Where appropriate, a coating that isimpermeable to the drug is placed over at least a portion of the deviceto further regulate the rate of release. When implanted subcutaneously,devices of the invention continuously release buprenorphine for anextended period of time with a pseudo or near zero order release rate.After an initial burst following implantation, release rates aretypically within about 10-20% of the steady state average. In someembodiments, the initial burst of buprenorphine released in vivo afterimplantation is reduced or minimized by prewashing the implantabledevices before implantation to remove surface buprenorphine. Prewashingmay be performed in any solution in which buprenorphine is soluble, forexample 30 minutes in ethanol or normal saline.

As used herein, “nonerodible matrix” refers to a polymeric carrier thatis sufficiently resistant to chemical and/or physical destruction by theenvironment of use such that the matrix remains essentially intactthroughout the release period. The polymer is generally hydrophobic sothat it retains its integrity for a suitable period of time when placedin an aqueous environment, such as the body of a mammal, and stableenough to be stored for an extended period before use. The ideal polymermust also be strong, yet flexible enough so that it does not crumble orfragment during use. Nonerodible matrices remain intact in vivo forextended periods of time, typically months or years. Drug moleculesencapsulated in the matrix are released over time via diffusion throughchannels and pores in a sustained and predictable manner. The releaserate can be altered by modifying the percent drug loading, porosity ofthe matrix, structure of the implantable device, or hydrophobicity ofthe matrix, or by adding a hydrophobic coating to the exterior of theimplantable device.

Typically, ethylene vinyl acetate copolymer (EVA) is used as thepolymeric matrix, but other nonerodible materials may be used. Examplesof other suitable materials include silicone, hydrogels such ascrosslinked poly(vinyl alcohol) and poly(hydroxy ethylmethacrylate),acyl substituted cellulose acetates and alkyl derivatives thereof,partially and completely hydrolyzed alkylene-vinyl acetate copolymers,unplasticized polyvinyl chloride, crosslinked homo- and copolymers ofpolyvinyl acetate, crosslinked polyesters of acrylic acid and/ormethacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride,polycarbonate, polyurethane, polyamide, polysulphones, styreneacrylonitrile copolymers, crosslinked poly(ethylene oxide),poly(alkylenes), poly(vinyl imidazole), poly(esters), poly(ethyleneterephthalate), polyphosphazenes, and chlorosulphonated polyolefines,and combinations thereof.

Implantable devices of the invention are typically formulated withbuprenorphine loading of about 10% to about 85%. Often, the devicesinclude about 50% to about 75% buprenorphine. Devices are sometimesformulated as compositions including about 75% buprenorphine and about25% EVA (33% vinyl acetate). In various embodiments, devices include anyof at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, or 85%buprenorphine. Devices may be produced using an extrusion process,wherein ground EVA is blended with buprenorphine, melted, and extrudedinto rod-shaped structures. Rods are cut into individual implantabledevices of the desired length, packaged, and sterilized prior to use.Other methods for encapsulating therapeutic compounds in implantablepolymeric, nonerodible matrices are well known to those of skill in theart. Such methods include, for example, solvent casting (see, e.g., U.S.Pat. Nos. 4,883,666, 5,114,719, and 5,601,835). A skilled artisan wouldbe able to readily determine an appropriate method of preparing such animplantable device, depending on the shape, size, drug loading, andrelease kinetics desired for a particular type of patient or clinicalindication.

Devices of the invention are suitable for sustained release ofbuprenorphine for treatment of opiate addiction or pain. As used herein,“sustained release” refers to the release of buprenorphine such that theblood concentration remains within the therapeutic range but below toxiclevels for an extended duration. Devices of the invention generallyexhibit near zero-order pharmacokinetics in vivo, similar to kineticsachieved with an IV drip, but without the need for external medicalequipment and personnel associated with intravenous methods. Generally,after implantation, the devices release therapeutically effectiveamounts of buprenorphine for periods of several months up to one year orlonger. Often, the duration of implantation, with continuous release ofbuprenorphine, is from about 3 months to about 2 years, about 3 monthsto about 1 year, about 3 months to about 9 months, or about 3 months toabout 6 months. In various embodiments, therapeutically effectiveamounts of buprenorphine are released for at least about 3, 6, 9, 12,15, 18, 21, or 24 months.

Multiple implantable devices may be used, or the size and shape of thedevices may be modified, to achieve a desired overall dosage.Implantable devices are often about 0.5 to about 10, more often about1.5 to about 5, most often about 2 to about 3 cm in length, and areoften about 0.5 to about 7, more often about 1.5 to about 5, most oftenabout 2 to about 3 mm in diameter. The release rate of implantabledevices may also be modified by changing the vinyl acetate content inthe EVA polymer matrix. The vinyl acetate content is often about 2 toabout 40, more often about 10 to about 35, most often about 30 to about35% by weight.

The desired dosage rate will depend upon factors such as the underlyingcondition for which buprenorphine is being administered, and thephysiology of a particular patient, but will be readily ascertainable tophysicians. For treatment of opiate addiction, buprenorphine isdesirably released at a rate that maintains plasma levels of the drug ata therapeutically effective level. Often, a desirable plasma level ofbuprenorphine for treatment of opiate addiction is in the range of about0.1 to about 70 ng/ml, more often about 1 to about 10 ng/ml, most oftenabout 1 to about 6 ng/ml. In various embodiments for treatment of opiateaddiction, buprenorphine is released from one or more devices in vivo ata rate that results in a plasma level of at least about 0.1, 0.5, 1, 2,3, 4, 5, 6, 8, 10, 15, 25, 50, or 70 ng/ml. For treatment of pain, atherapeutically effective amount of buprenorphine is typically about 0.1to about 5 mg/day, sometimes about 0.2 to about 1 mg/day, often about0.3 mg/day, but may be modified depending upon the nature of the paincondition being treated and the particular patient involved. In variousembodiments for treatment of pain, one or more devices are used that arecapable of releasing at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4,or 5 mg/day in vivo or in vitro. As used herein, “therapeuticallyeffective amount” or “therapeutically effective level” refers to theamount of buprenorphine that will render a desired therapeutic outcome(i.e., reduction of self-administration of nonprescribed drugs, oranalgesic relief of pain).

Methods of the Invention

The invention provides methods for treatment of opiate addiction andpain. Methods of the invention include subcutaneous administration ofone or more polymeric implantable devices which include buprenorphineencapsulated within a biocompatible, nonerodible polymeric matrix suchas EVA, and release of buprenorphine in a controlled manner over anextended period of time through multiple pores that open to the surfaceof the implantable device(s). Often, implantable devices are producedvia an extrusion process, as described above.

Implantable devices are administered by subcutaneous implantation to anindividual in need of treatment. As used herein, “individual” refers toa mammal, typically a human in need of treatment for opiate addiction orpain. Generally, implantable devices are administered by subcutaneousimplantation at sites on the upper arm, back, or abdomen of anindividual. Other suitable sites for administration may be readilydetermined by a medical professional. Multiple implantable devices maybe administered to achieve a desired dosage for treatment.

Typically, in a method for treatment of opiate addiction, an implantabledevice or devices are administered that will release buprenorphine at arate that will maintain a therapeutically effective plasma level for anextended period of time of at least about 3 months. When multipledevices are administered, the combination of the devices releasesbuprenorphine at a rate that will achieve a therapeutically effectiveplasma level. A therapeutically effective plasma level for treatment ofopiate addiction is often about 0.1 to about 70 ng/ml, more often about1 to about 10 ng/ml, most often about 1 to about 6 ng/ml. Often,sustained release at this dosage rate occurs for about 3 months to about1 year or longer (e.g., at least about 3, 6, 9, or 12 months). As usedherein, “opiate addiction” or “opiate dependency” refers to dependenceby an individual on an opiate substance which is treatable byadministration of a substitute substance, such as methadone orbuprenorphine. It is anticipated that the implantable devices of theinvention will alleviate compliance and diversion problems encounteredwith traditional methadone treatment regimens, as described above.

Further, in accordance with the present invention, a method ofalleviating pain is provided which includes subcutaneous administrationof an implantable nonerodible polymeric device which releases ananalgesically effective amount of buprenorphine in a controlled mannerfor an extended period of time, i.e. about 3 months to about 1 year(e.g., at least about 3, 6, 9, or 12 months) or longer, to an individualexhibiting pain. An implantable device is chosen for a particularpatient or pain indication such that an analgesically effective amountof buprenorphine will be continuously released. As used herein, the term“analgesically effective amount” refers to an amount of buprenorphinesufficient to achieve a reduction in or elimination of pain in amammalian subject without loss of consciousness. The effectiveness ofanalgesia provided by an analgesic substance can be assessed by methodsthat are well known to those skilled in the art. For example, U.S. Pat.No. 6,228,863 describes assessment by direct measurement in humanpatients or by the use of one or more surrogate measures. Directmeasurement may include scoring an analgesic questionnaire reported bypatients at serial times following administration of the analgesicsubstance. Summary measures of analgesia include the sum of painintensity difference (SPID) and total pain relief (TOTPAR). Surrogatemeasures for determining analgesic effectiveness in human subjectsinclude assessment of sedation, respiratory rate and/or pupil size, andvisual analogue scale for drug effect. Effectiveness of analgesia mayalso be assessed using animal models. For example, U.S. Pat. No.4,599,342 describes a mouse hot plate test and a phenylquinone writhingtest model for assessing the extent of analgesia.

The method of alleviating pain according to the present invention isapplicable to the treatment of all pain conditions which requirecontinuous administration of an analgesic substance, e.g., postoperativepain, cancer pain, arthritic pain, lumbosacral pain, musculoskeletalpain, neuropathic pain, etc. This list, however, should not beinterpreted as exhaustive. It is contemplated that the method of theinvention will improve compliance with dosing regimens for therapeuticpain relief, while reducing the amount of opiate substances that areavailable for diversion to nonintended users, i.e., drug addicts. Longterm continuous release should also reduce or eliminate the peaks andtroughs of blood analgesic concentration associated with otherformulations such as oral dosage forms. Typically, the steady staterelease rate of buprenorphine used for pain relief methods is from about0.1 to about 5, sometimes about 0.2 to about 1, often about 0.3 mg perday.

In any of the above methods, the length of time during whichbuprenorphine is continuously administered may be extended byreimplanting additional implantable devices in an individual receivingtreatment before or after plasma levels of buprenorphine begin todecline, to maintain buprenorphine at the desired steady state level.

Kits

The invention also provides kits for use in treatment of opiateaddiction or pain. The kits include at least one implantable,nonerodible device of the type herein described, capable of deliveringlong-term therapeutic levels of buprenorphine, in suitable packaging,along with instructions providing information to the user and/or healthcare provider regarding subcutaneous implantation and use of the systemfor treating drug dependence or pain. Kits may also include literaturediscussing performance of the implantable devices of the invention. Kitsinclude a delivery system, i.e., one or a multiplicity of implantabledevices, capable of providing sustained release of therapeutic levels ofbuprenorphine for at least about 3 months. Kits for treatment of opiateaddiction typically contain a polymeric, nonerodible delivery systemcapable of continuously releasing buprenorphine at a rate sufficient toachieve a therapeutically effective plasma level of about 0.1 to about70, about 1 to about 10, or about 1 to about 6 ng/ml for at least about3 months. Kits for treatment of pain typically contain a delivery systemcapable of releasing a total continuous analgesically effective dosageof about 0.1 to about 5, about 0.2 to about 1, or about 0.3 mgbuprenorphine per day for at least about 3 months. In kits of theinvention, implantable devices may be preloaded into devices such as,for example, syringes or trocars, capable of administering them bysubcutaneous implantation into patients.

EXAMPLES

The following examples are intended to illustrate but not limit theinvention.

Example 1 Materials and Methods

Materials

The following materials were used:

-   -   Buprenorphine HCl, 99.3%, supplied by Macfarlan Smith Limited,        Wheatfield Road, Edinburgh, EH 11 2QA    -   Buprenorphine base, supplied by Diosynth B.V. Vlijtseweg 130,        7317 AK Apeldoorn, The Netherlands    -   Buprenorphine HCl, supplied by Diosynth B.V. Vlijtseweg 130,        7317 AK Apeldoorn, The Netherlands    -   Methanol-ChromAR, HPLC grade, supplied by Mallinckrodt, St.        Louis, Mo.    -   Acetonitrile, HPLC grade, supplied by Mallinckrodt, St. Louis,        Mo.    -   Sodium lauryl sulfate, 99%, supplied by Sigma Chemicals, St.        Louis, Mo. EVA, 33% vinyl acetate, supplied by Equistar        Chemicals, LP, Houston, Tex.    -   Tower Plasti-Peel pouches, Catalog #30307PN, supplied by DRG        Medical Packaging, Mundelein, Ill.

Preparation of Implantable Devices

Buprenorphine is available as a salt (HCl) and as a free base. Theimplantable device is intended to release drug over a 3-month period orlonger, so preliminary studies were performed to select the form ofbuprenorphine suitable for sustained release. Buprenorphine wasincorporated at 50% drug load in the copolymer, using the free base formand the HCl salt. Extruded rods were prepared and comparative in vitroevaluations were conducted to select the drug form, based on the resultsof these studies.

Implantable devices were prepared using an extrusion process. As aresult of initial loading experiments with lactose, two sets ofextrusion parameters were identified that produced implantable deviceswith a smooth exterior finish and homogeneous drug content. Theextrusion parameters were as follows:

Set 1 Zone 1: 210° F.

-   -   Zone 2: 230° F.    -   Zone 3: 210° F.    -   Die: 214° F.    -   RPM: 67    -   Die orifice: 2.18 mm        Set 1 parameters were used for the preparation of rods        incorporating 50% buprenorphine free base and HCl salt.

Set 2 Zone 1: 210° F.

-   -   Zone 2: 230° F.    -   Zone 3: 230° F.    -   Die: 240° F.    -   RPM: 40    -   Die orifice: 1.95 mm        Set 2 parameters were used for the preparation of rods        incorporating 75% buprenorphine HCl salt, which were used for in        vitro and in vivo studies as described below.

The ground copolymer and compound to be incorporated were used asreceived from the manufacturer. The extruded rods were cut into uniformlengths of 25 mm, packaged in polyester/Tyvek bags, heat sealed, andshipped to Steris/Isomedix (Libertyville, Ill.) for terminalsterilization by gamma irradiation.

HPLC Assays

HPLC analysis was used to determine the rate of in vitro release ofbuprenorphine from buprenorphine-containing implants. Chromatography wasperformed using a Waters Novapak C-18 (150 mm×3.9 mm, SN. E5003B) columnand 0.05 M sodium acetate, pH 5 (Solution A) and a mixture ofmethanol/acetonitrile (2:1 v/v) (Solution B) as the mobile phase, at aratio of 35%A and 65%B and a flow rate of 1 ml/min. The injection volumewas 1004 Detection was accomplished by means of a UV/VIS (Waters Model490) detector at a wavelength of 285 nm. Instrument control and dataacquisitions were facilitated using a Waters Millennium (V 2.15)software package. The external calibration was obtained usingbuprenorphine standard solutions prepared in 2:1 (v/v) acetonitrile:methanol.

The calibration curve for the buprenorphine standard over aconcentration range of 2.5-500 μg/ml indicated linearity, with r2 valuesgreater than 0.99.

LC/MS/MS Assay

An LC/MS/MS method was used to determine levels of buprenorphinereleased from the implants in vivo.

Buprenorphine

Dog plasma (0.500 ml) containing buprenorphine and a D4-buprenorphineinternal standard was extracted with hexane/isoamyl alcohol. Followingcentrifugation, transfer of the organic layer and evaporation, the driedextract was derivatized with pentafluoropropionic anhydride (PFPA).After the reaction, the excess reagent was evaporated and an aliquot ofthe reconstituted extract was injected onto a SCIEX API III PlusLC-MS-MS apparatus in positive ion mode equipped with an HPLC column.Peak areas of the m/z 596 to 564 product ion of buprenorphine-PFP weremeasured against the m/z 600 to 568 product ion of the internal standardin MRM mode. Quantitation was performed using a weighted linear leastsquares regression analysis generated from spiked plasma calibrationsamples.

Norbuprenorphine

Dog plasma (0.500 ml) containing norbuprenorphine and aD3-norbuprenorphine internal standard was basified and extracted withethyl acetate. Following evaporation, the dried extract was derivatizedwith acetic anhydride. After the reaction, the excess reagent wasevaporated and an aliquot of the reconstituted extract was injected ontoa SCIEX API III-Plus LC-MS-MS apparatus equipped with an HPLC column.Peak areas of the m/z 586 to 498 product ion of the norbuprenorphinederivative was measured against the peak areas of the m/z 589 to 501product ion of the internal standard. Quantitation was performed usingthe peak areas of the m/z 589 to 501 product ion of the internalstandard. Quantitation was performed using a weighted linear leastsquares regression analysis generated from fortified plasma calibrationsamples.

Example 2 In Vitro Characterization of Extruded Implantable Devices

Extruded rods prepared as described above were characterized for totaldrug load and for rate of drug release.

Assessment of Drug Loading

Extruded rods were accurately weighed, placed in tightly closedborosilicate glass jars containing 50 ml of methanol, and continuouslystirred at room temperature. Sample aliquots were removed periodicallyand analyzed by HPLC. Initial experiments indicated that theincorporated compounds were completely extracted within 24 hr.Irradiated and nonirradiated rods were compared side by side.

Drug loading studies indicated that the physical mixtures werehomogeneous and contained the estimated quantities of buprenorphine.Table 1 shows the recovery for the free base (FB) and HCl salt at 50%loading. Table 2 shows the recovery of buprenorphine HCl at 75% loading,and indicates that the average drug load before and after gammaradiation was >75%.

TABLE 1 Recovery of buprenorphine at 50% drug loading. Sample 1 Sample 2Average Drug (% drug load) (% drug load) (% drug load) Buprenorphine HCl51.0 49.6 50.3 Buprenorphine FB 45.5 46.5 46.0

TABLE 2 Recovery of buprenorphine HCl at 75% drug loading. BeforeRadiation After Radiation (% drug load) (% drug load) Average = 77.3Average = 75.5 SD = +/−4.2 SD = +/−3.6

Assessment of Drug Release

Experiments were performed to determine the rate of buprenorphinereleased from the extruded rods. The medium for these studies was 0.5%sodium lauryl (dodecyl) sulfate (SDS). The preweighed rods were placedin 100 ml screw cap jars containing 50 ml of medium and placed on anorbital shaker. The orbital shaker was housed in an incubator maintainedat 37° C. Sampling of the medium was performed by replacing the mediaperiodically. The samples obtained were analyzed by HPLC.

Comparison of the in vitro release of buprenorphine base and salt formindicated that daily release for the HCl salt, after an initial burst,was closer than that of the free base to the desired range of about 1mg/day (FIG. 1). Thus, the HCl salt was selected for further studies.

Example 3 In Vivo Evaluation of Drug Loaded Implantable Devices

Three female beagle dogs were administered two sterilized implantabledevices each containing 75% buprenorphine HCl in EVA containing 33%vinyl acetate, as described above (2 mm diameter×2.6 cm length rods).Implantable devices were administered by subcutaneous injection to thedorsal region of each dog using a trocar. Blood samples were withdrawnperiodically over a period of 84 days and frozen. The frozen sampleswere analyzed by LC/MS/MS for content of buprenorphine andnorbuprenorphine (the major metabolite).

After an initial burst, the mean buprenorphine plasma levels weremaintained around 0.75-1.0 ng/ml through day 84. The mean buprenorphineand norbuprenorphine levels were similar in all three dogs. The peakconcentration of buprenorphine in the plasma ranged from 2.41 to 6.32ng/ml. After the initial burst effect, a slow decrease in plasmaconcentration of buprenorphine was observed for all the dogs. On day 84,plasma concentration of buprenorphine ranged from 0.72 to 0.99 ng/ml. Nosigns of toxicity or irritation and/or inflammation at the sites ofimplantation were observed in any of the dogs. Further, novascularization or minimal fibrous capsule formation were observed. Theplasma concentration of buprenorphine over time for this experiment isshown in FIG. 2.

Example 4 Long Term Delivery of Burenorphine via an Implantable DeliverySystem In Vivo

In vivo release of buprenorphine from polymeric implantable devices wasinvestigated in toxicology studies in beagle dogs over an eight monthperiod of time. Four dosage groups were treated with 2, 8, 16, or 24implantable devices (rod-shaped devices containing 25% buprenorphine HCland 75% EVA with 33% vinyl acetate, as described in Example 3).Implantable devices were administered subcutaneously in the dorsalregions of dogs via trocar under sterile conditions. Blood samples werecollected from the jugular veins at various times for 8 months postimplantation. Plasma concentrations of buprenorphine were quantified byLC/MS/MS. Animals were monitored for complications including irritation,inflammation, or infection at the treatment site. Pharmacokineticparameters observed for the different dosage groups are represented inTable 3.

TABLE 3 Pharmacokinetic Parameters Calculated from Plasma ConcentrationsMean Mean Half-Life to Number of Mean C_(max) ^(a) t_(max) ^(b) C_(ss)^(c) C_(ss) Number of Implants (ng/mL) (day) (ng/mL) (weeks) Dogs, n 24.4 1 0.81 ± 0.1  0.7 3 8 21.6 1 3.2 ± 0.4 2 2 16 36.1 1 4.6 ± 0.5 2 224 74.6 1 9.3 ± 0.7 2 10 ^(a)Maximum concentration of buprenorphineachieved in plasma ^(b)Time of maximum plasma concentration ofbuprenorphine ^(c)Mean steady-state plasma concentration

After an initial burst, pharmacokinetics were linear and doseproportional with 2 and 8 implantable devices, and were saturable andnonlinear with 16 and 24 devices (FIG. 3). Steady-state concentrationsof 0.81±0.1 and 3.2±0.4 ng/ml were achieved within 3 weeks with 2 and 8devices, respectively (FIG. 4). Steady-state concentrations of 4.6±0.5and 9.3±0.7 ng/ml were achieved within 8 weeks with 16 devices and 10weeks with 24 devices, respectively. Upon reaching steady state,buprenorphine levels remained steady, with a concentration variabilityof about 10-20%, until 8 months post implantation, at which time theimplantable devices were removed. Norbuprenorphine plasma concentrationsremained below detectable levels. The additional time required to reachsteady state with 16-24 implantable devices may be attributable tolimited diffusion of the drug due to saturation of the space between thedevices and blood capillaries, or due to saturation of capillaryabsorptive surface area.

No significant systemic or local (implantation site) adverse effectswere observed in any of the dogs. Minor irritation at the treatment sitewas observed in three dogs. No adverse behavioral effects were observedother than lethargy on the first day after implantation for animalsreceiving the maximum dosage (i.e., 24 devices). Upon removal of thedevices after 8 months, no areas of necrosis or visible vascularizationwere observed in the tissue that had been surrounding the devices.

Although the foregoing invention has been described in some detail byway of illustration and examples for purposes of clarity ofunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practiced without departingfrom the spirit and scope of the invention. Therefore, the descriptionshould not be construed as limiting the scope of the invention, which isdelineated by the appended claims.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety.

1-28. (canceled)
 29. A method for treatment of pain, comprisingadministering at least one implantable device subcutaneously, saidimplantable device comprising buprenorphine and a biocompatible,nonerodible polymeric matrix, wherein said buprenorphine is encapsulatedwithin said matrix, wherein said at least one implantable devicescontinuously releases buprenorphine in vivo over a sustained period oftime through pores that open to the surface of said matrix at a steadystate rate of about 0.1 to about 5 mg per day.
 30. A method according toclaim 29, wherein said at least one implantable device comprises amultiplicity of individual implantable devices, and wherein thecombination of said implantable devices continuously releasesbuprenorphine in vivo over a sustained period of time at a steady staterate of about 0.1 to about 5 mg per day.
 31. A method according to claim29, wherein each of said at least one implantable devices issubcutaneously implanted at a site selected from the group consisting ofthe upper arm, the back, and the abdomen.
 32. A method according toclaim 29, wherein each of said at least one implantable devicescomprises EVA.
 33. A method according to claim 32, wherein each of saidat least one implantable devices comprises about 10 to about 85%buprenorphine.
 34. A method according to claim 29, wherein saidsustained period of time is at least about 3 months.
 35. (canceled) 36.A kit for use in treatment of pain, comprising at least one implantabledevice comprising buprenorphine and a biocompatible, nonerodiblepolymeric matrix, wherein said buprenorphine is encapsulated within saidmatrix and wherein when said implantable device is subcutaneouslyimplanted in a mammal, said buprenorphine is continuously released invivo over a sustained period of time through pores that open to thesurface of said matrix at a steady state rate of at least about 0.1 mgper day, and instructions for use.